Aging is the greatest risk factor for most chronic diseases, including diabetes, cardiovascular disease, cancer, Alzheimer?s Disease (AD) and related dementias. However, centenarians and super-centenarians have a lower incidence and severity of these age-related diseases including AD. As part of the NIA-funded U19 entitled ?Genetic Variant-based Drug Discovery Targeting Conserved Pathways of Aging?, we are exploring the genetic differences between successfully aged, healthy centenarians and individuals with no family history of extreme longevity. Using the centenarian resource at the Albert Einstein College of Medicine, we identified rare genetic variants associated with conserved mechanisms of healthy longevity and subsequently are using them as leads for developing and testing small molecules targeting the pathways affected by these rare variants. Interestingly, our results thus far indicate that human longevity and healthy aging correlate with sequence variants in key genes in pathways previously identified as driving extended lifespan in model organisms. For example, insulin/IGF-1 signaling (IIS) is a pathway that regulates lifespan in eukaryotes and there is overwhelming evidence that dampening IIS increases lifespan and health span in diverse species including nematodes, flies, and mice. Our U19 team identified two missense rare variants in the IGF-1 receptor gene (IGF1R): A37T (M1) and R407H (M2) are enriched in Ashkenazi Jewish centenarians compared to younger elderly controls. These mutations reduced the phosphorylation of AKT by IGF-1R in human cells, illustrating reduced activity and thereby dampened IIS. Furthermore, the mutant receptors (M1 and M2) diminish AKT phosphorylation in a domimant fashion. Although these mutant receptors had no effect on activation of MAPK signaling, they signficantly increased the level of 4EBP1 compared to the WT IGF-1R. Consistent with these in vitro results, muscle-specific expression of a mutant human IGF-1R gene that prevents activation of AKT and significantly elevates 4EBP1 expression, extended the lifespan and health span pf progeroid mice (Ercc1-/?;Igf1R-SKM). Recently, we engineered a mouse (Igf1R-cent) harboring the M2 mutation, which are being characterized (measures of health span, and lifespan). Here, we propose to use the Igf1R-cent and Igf1R-SKM mice in a progeroid (Ercc1-/?) background to test the hypothesis that reduced IIS signaling will delay the onset or reduce the severity of AD and related dementias, explaining at least in part why centenarians are spared from AD. The proposed experiments will be accomplished in one year through the use of AAV-mediated gene transfer of A and Tau into the CNS of Igf1R-cent and Igf1R-SKM Ercc1-/? mice, which yields AD-related pathology cognitive decline within 3 months. The proposed experiments will reveal if systemic aging (progeria) exacerbates AD and whether a sequence variant in IGF-1R identified in centenarians attenuates this. If reduced IIS signaling delays or attenuates AD pathology and functional decline, this has the potential to yield new approaches to therapy.